Sarcomatoid versus rhabdoid dedifferentiation and histologic grade-specific outcomes in metastatic clear cell renal cell carcinoma (mccRCC): A multi-institutional analysis of 514 patients.

Abstract

456 Background: WHO/ISUP grade 4 RCC, defined by rhabdoid or sarcomatoid dedifferentiation or extreme nuclear pleomorphism, is associated with aggressive biology and poor outcomes. While sarcomatoid dedifferentiation is recognized as a particularly adverse prognostic phenotype, the clinical impact of individual grade patterns remains uncertain. Using a large multi-institutional dataset, we examined clinical outcomes according to histologic grade and dedifferentiation status. Methods: Patients with mccRCC treated with first-line nivolumab and ipilimumab were retrospectively identified. Patients were categorized based on tumor ISUP grade and dedifferentiation status: sarcomatoid, rhabdoid, both sarcomatoid and rhabdoid (S+R), ISUP grade 4 without sarcomatoid or rhabdoid (Gr4nonS/R) and ISUP Grade ≤3. Disease characteristics, time to next treatment (TTNT) and overall survival (OS) were compared between each ISUP Grade 4 category and ISUP Grade ≤3. Multivariable models adjusting for IMDC risk, number of metastatic sites, and nephrectomy status assessed the independent effects of sarcomatoid and rhabdoid dedifferentiation. Results: Among 514 patients, 197 had ISUP Gr≤3 disease, 179 had grade 4 disease (61 with sarcomatoid, 67 with rhabdoid, 51 with S+R, 35 with gr4nonS/R), while 103 had ccRCC but not evaluable histological grade. Patient characteristics were comparable across cohorts, except for higher IMDC risk, and a greater frequency of de-novo metastatic disease in sarcomatoid (p = 0.004 and p = 0.01, respectively), a higher proportion of females in rhabdoid (p = 0.01), and more de-novo metastatic disease in S+R (p = 0.009), compared with the Gr≤3 reference group. While TTNT was comparable across histologic grade groups, pairwise analyses for OS using ISUP Gr ≤3 (5.4 yrs [95%CI 4.5, 7.7]) as reference, yielded worse median OS in sarcomatoid (2.9 yrs [95% CI 2.0, 3.8], p = 0.01), but not other grade 4 categories: R (Not reached [NR], [95% CI 3.2, NR], p = 0.84), S+R (9.1 yrs [95% CI 1.9, 9.1] p = 0.12), or Gr4nonS/R (6.5 yrs [95% CI 2.9, NR], p = 0.86). In multivariable analyses, sarcomatoid (Yes/No) was independently associated with worse OS (HR 1.56, 95% CI: 1.13, 2.16; p = 0.007), whereas rhabdoid features (Yes.no) showed no such association (HR: 0.97, 95% CI: 0.68, 1.37; p = 0.84). Conclusions: Sarcomatoid dedifferentiation was independently associated with worse OS, whereas rhabdoid features did not show a comparable adverse effect in mccRCC treated with first line nivolumab/ipilimumab. Findings reinforce the prognostic weight of sarcomatoid dedifferentiation despite treatment with nivolumab/ipilimumab and suggest a less aggressive phenotype and a female predilection for rhabdoid differentiation, which requires further clinical and translational investigation.